Received March 14, 2017; Revision received May 11, 2017
In MCF-7 human breast carcinoma cells, α5β1 integrin
hyperexpression, which was accomplished by transduction of a
full-length α5 integrin cDNA, increased by about 50-70% the
number of cells, survived during 48-72 h cell treatment with
doxorubicin. Up-regulation of α5β1 reduced the level of the
apoptogenic p53 protein and p21 cell cycle inhibitor, but enhanced the
activity of Akt and mTOR protein kinases. In addition to these
findings, we observed a significant decrease in the activity of both
isoforms of phosphokinase Erk1/2, which is known to play a key role in
cell viability pathways, including pathways alleviating stress damages
caused by distinct antitumor drugs. Diminished Erk activity
accompanying the rise of drug resistance can be explained by an
“atypical” function of this kinase, which, in the cells
studied, promotes an enhanced rather than reduced sensitivity to
doxorubicin. To verify this suggestion, the effect of a specific Erk
inhibitor, PD98059, on the resistance to doxorubicin of control and
α5 cDNA-transduced MCF-7 cells was investigated. The data showed
that suppression of Erk activity increased the resistance of control
cells (transduced with an “empty” vector) to a level higher
than that demonstrated by the α5 cDNA-transduced cells. The
highest level of resistance was observed in α5β1-trancduced
cells treated with PD98059. Akt and mTOR kinase inhibitors had little
if any effect on doxorubicin resistance of α5 cDNA-transduced
MCF-7 cells. The data show for the first time that integrin
α5β1 can stimulate drug resistance of tumor cells through a
mechanism based on the inhibition of protein kinase Erk. From a more
general view, the results of this investigation suggest that signal
protein kinases can perform in tumor cells “non-canonical”
functions, opposite to those, which are the basis for using kinase
inhibitors in targeted cancer therapy. It follows that if a protein
kinase is supposed to be used as a target for such therapy, it is
important to explore its features in the particular tumor prior to the
onset of treatment.
KEY WORDS: integrins, tumor growth, drug resistance, Erk protein
kinase, signaling